- 作者: Franqoise Bergametti, Julie Bianchi, Catherine Transy
- 作者服務機構: Unit de Recombinaison et Expression Genetique (INSERM U163), Institut Pasteur , Paris , France
- 中文摘要: --
- 英文摘要: mediated stabilization of wild-type × protein. These ×protein derivatives thus provide the basis for the devel-opment of therapeutic agents that antagonize × functionthrough competitive inhibition of ×-DDB1 interaction.The hepatitis B virus × protein is a multifunctional pro-tein that is essential for naturalinfection and has alsobeen implicated in liver cancer development. Previousstudies have identified the DDB1 subunit of the dam-aged-DNA binding complex as a critical partner of × pro-tein in the infection process, ×-mediated cytotoxicity andstability of the viral protein. Here, we investigated thestructural and functional constraints of ×-DDB1 interac-tion using various mutational analyses. Our data showthat the interaction interface of × with DDB1 is confinedto a 15-residue epitope. All substitutions responsible forloss of binding mapped to this core-binding domain. Incontrast, a marked increase in affinity for DDB1 resultedfrom substitutions at clustered positions lying close tothe DDB1-binding epitope and correlated with loss ofapoptotic potential. Selection of mutations in DDB1 thatpartially rescue the binding defect of an × mutant gavefurther insight into the contacts established between thetwo proteins. Importantly, both the core-binding domainof × and the gain-of-affinity × mutants inhibited DDB1-
- 中文關鍵字: --
- 英文關鍵字: Hepatitis B virus, X protein, UV-damaged DNA-binding protein, Protein-protein interaction